One doctor’s perspective On the state of HIV TREATMENT
Positively Aware Joe Gallant
By Joel Gallant, MD, MPH

Antiretroviral therapy (ART) options continue to expand and improve, making antiretroviral therapy (ART) easier, better tolerated, and more convenient. In this article, I’ll discuss my own opinions on options for initial therapy, and what’s in the pipeline.

Initial Therapy

There’s a wealth of potential options for first-line therapy, but only a few combinations that we’re now starting with on a regular basis. Integrase inhibitors are hot these days, because in trial after trial, they’re either as good or better than older regimens, with clear tolerability advantages. Speaking for myself, there are just a handful of “go-to” regimens for patients starting ART without baseline resistance, listed here in no particular order.

  • Stribild
  • Triumeq
  • Tivicay plus Truvada
  • Boosted Prezista plus either Truvada or Epzicom

Of course, I have patients on many other first-line regimens. There’s no reason to switch therapy in someone doing well on Atripla, Complera, Viramune, or Isentress, for example. But I generally stick with one of the choices mentioned above if I’m starting ART for the first time. Here’s why.

Atripla is an effective medication that has served us well for many years, but the early and usually temporary neuropsychiatric side effects (vivid dreams, dizziness, mood and cognitive changes) have always been a nuisance—one that we don’t have to put up with anymore using other combinations. Some people have lingering side effects: dizziness, depression, difficulty focusing or concentrating, or sleep changes that persist long after the more intense early side effects have resolved. These changes may be subtle, and it’s often impossible to know whether they’re caused by Atripla without making a switch. I leave people on Atripla if they’re doing well without side effects, but I don’t use it any longer in people starting ART.

Viramune becomes a fine drug after the first month or two, but it has potentially serious and even life-threatening toxicities during the first few weeks, especially in people with high CD4 counts. Now that we’re starting ART at high CD4 counts, Viramune isn’t a great choice for most people to start with. But there’s no need to switch therapy in people doing well on Viramune—even people with high CD4 counts—unless they prefer a single-tablet regimen.

Isentress is a great drug: it’s effective, well tolerated, and has few drug interactions. Its only downsides are that it’s taken twice a day and isn’t available as part of a single-tablet regimen, unlike the other two integrase inhibitors. If you don’t mind twice-daily dosing or are already taking other twice-a-day medications, there’s no reason to switch, but for those who would prefer something more convenient, Stribild and Triumeq offer easier alternatives.

Complera is a well tolerated single-tablet regimen. I have many patients taking it, and have often used it as a regimen to switch to in people who wanted something simpler or easier to tolerate. It’s still a good choice for initial therapy in people with baseline viral loads below 100,000, provided they’re not taking drugs that lower stomach acid and can consistently take it with a full meal. However, those limitations don’t apply to integrase inhibitor-based regimens, making them more attractive options for many people.

So how do I choose among my favorite regimens?

Stribild is a great choice for people who want an easy, single-tablet regimen, even with high viral loads or low CD4 counts. It contains an integrase inhibitor (elvitegravir) along with a pharmacologic “booster” (cobicistat). I avoid it in people with kidney disease or those who need drugs that can’t be taken with cobicistat, which is similar to Norvir in terms of drug interactions.

Triumeq is another very effective single-tablet regimen. Like Stribild, it includes an integrase inhibitor (dolutegravir). Unlike Stribild, it does not need a booster, which means fewer concerns about drug interactions. Triumeq also contains a different nucleoside “backbone”: abacavir/lamivudine rather than tenofovir/emtricitabine. Abacavir has no kidney toxicity, but there is still a lingering debate about whether it increases the risk of heart attack. Current guidelines recommend avoiding abacavir (including Triumeq) if you have high risk for heart disease. Pre-screening for abacavir hypersensitivity with an HLA B*5701 test is necessary before starting Triumeq.

Tivicay plus Truvada: This is a good two-pill option for people who want to take the dolutegravir (Tivicay) included in Triumeq without the abacavir/lamivudine (Epizcom) backbone. This would usually be due to high cardiac risk or a positive HLA B*5701 test indicating abacavir hypersensitivity.

Boosted Prezista plus either Truvada or Epzicom: I generally choose a boosted protease inhibitor (PI) when adherence is uncertain: in people with substance abuse or mental health issues, people who miss lots of clinic appointments, people with no prior experience taking long-term medications, or the very young. That’s because it’s almost impossible to develop PI resistance on a boosted PI, no matter how badly you screw up. There’s always the option of switching to a single-tablet regimen later, once it’s clear that non-adherence won’t be a problem. Fortunately, PI-based regimens aren’t as complicated as they used to be. Up to now, we’ve been boosting Prezista with a separate tablet of Norvir, but you are now able to take a two-pill-per-day regimen using Prezcobix (a new Prezista/cobicistat combination pill) plus either Truvada or Epzicom. A single-tablet Prezista-based regimen is also in the works. EvoTaz (Reyataz/cobicistat) is also now available, but of the available PIs, I generally prefer Prezista because it’s a little better tolerated than Reyataz. I should add that dolutegravir-containing regimens (Triumeq, or Tivicay + Truvada) may also be good choices for people with uncertain adherence. We haven’t seen dolutegravir resistance yet when it’s used for initial therapy, but it’s too early to say whether its “resistance barrier” is as high as that of a boosted PI.

What’s new for initial therapy

The next big thing will probably be tenofovir alafenamide (“TAF”). Like the tenofovir DF that we use now (TDF, Viread), TAF is a “pro-drug,” meaning it doesn’t get turned into active tenofovir until after it’s absorbed. TAF achieves higher tenofovir levels within cells than TDF, but blood levels are lower. This translates into reduced toxicity (kidney and bone), with greater activity against resistant virus. There will be new versions of Truvada, Stribild, and Complera using TAF instead of TDF, as well as entirely new combinations, such as a single-tablet PI regimen (darunavir/cobicistat/emtricitabine/TAF). In fact, TAF could completely replace TDF for all purposes, although that will ultimately depend on pricing and the whims of insurance companies.

Treatment-experienced patients

Because there are now so few people with HIV that’s “untreatable” with the available drugs, drug companies have less interest in developing drugs for what we used to call “salvage therapy.” Most drugs in development are intended for first-line use, which is where the money is. That being said, there is some good news for people with extensive drug resistance.

At double the usual dose, Tivicay is sometimes active against virus that’s resistant to Isentress and elvitegravir, the integrase inhibitor in Stribild. The more integrase mutations you have, the less likely you are to respond to Tivicay, so don’t stay on Isentress or Stribild if they’re not keeping your viral load undetectable. Integrase genotype tests will tell you whether Tivicay still has activity. Avoid accumulating new integrase mutations by getting off that class of drugs until you can combine Tivicay with at least one other active drug.

Because it achieves higher tenofovir levels within cells, TAF, discussed above, is more active than TDF against NRTI-resistant virus, including some TDF-resistant virus.

Doravirine, an investigational non-nucleoside reverse transcriptase inhibitor (NNRTI), has activity against common mutations that cause resistance to the existing NNRTIs (Viramune, Sustiva, and perhaps even Intelence).

Finally, there are new drugs in development with entirely new mechanisms of action, interfering with the very first stage of viral entry. BMS-663068 blocks the attachment of the virus to the CD4 receptor, and ibalizumab is a monoclonal antibody that binds to the CD4 receptor. These attachment inhibitors have promise for people who have run out of other options.

Other NRTIs, integrase inhibitors, and protease inhibitors are also being developed, including long-acting drugs that could be given by intermittent injections. For example, the combination of the integrase inhibitor cabotegravir and a long-acting version of rilpivirine (Edurant) could be given by intermittent injection, and cabotegravir is also being studied as a PrEP agent, given by injection every three months.

Drug regimens may soon get simpler for people with extensive resistance. For example, it may not be long before someone with 3-class resistance to NRTIs, NNRTIs, and PIs could take a regimen consisting of a single tablet of the TAF-version of Stribild plus a single tablet of Prezista. That two tablet “salvage” regimen would be a remarkable improvement over the more complex regimens that many treatment-experienced patients are taking now.

JOEL GALLANT is Medical Director of Specialty Services at Southwest CARE Center in Santa Fe, New Mexico, adjunct professor of medicine at the Johns Hopkins School of Medicine, and clinical professor of medicine at the University of New Mexico. He treats patients and conducts clinical trials on the treatment of HIV infection. He is Immediate Past-Chair of the HIV Medicine Association and is on the Board of Directors of the IAS-USA. He is a member of the IAS-USA Antiretroviral Guidelines panel and the IDSA/HIVMA HIV Primary Care Guidelines panel. He authored 100 Questions and Answers about HIV and AIDS and has an interactive question and answer blog at hivforum.tumblr.com.